Diseases caused by unicellular parasitic organisms belonging to the eukaryotic phylum Apicomplexa are notoriously difficult to treat. The most prominent organisms in this phylum are Plasmodium, the causative agent of malaria, and the AIDS-related pathogens, Toxoplasma and Cryptosporidium. Current treatments for these organisms, when they exist, are threatened by the emergence of drug resistance or are of limited efficacy. The consequence is that millions of people, primarily children, die annually. New therapeutics is needed. All good therapeutic targets have one feature in common;the target molecule/pathway in the pathogen is sufficiently distinct from similar molecules/pathways in the host such that therapeutic compounds can be discriminated between. Apicomplexan parasites, like us, are eukaryotic organisms. Thus, there are fewer novel targets available for therapeutics to discriminate between. However, apicomplexan parasites have had an eventful evolutionary history involving endo-symbiosis of a red alga and numerous gene transfers from the alga and other bacteria. These evolutionary distant sources of genetic material can provide potential new therapeutic targets. The challenge is to find them. A systematic, evolutionary genomic search of the metabolic, immune evasive and host adaptive capabilities of apicomplexan pathogens is proposed. The experimental plan described here exploits the complex evolutionary history of the Apicomplexa and the increased availability of genome sequence data for numerous parasites and their human host. The origins of novel parasite capabilities and the types of innovation and adaptation to host created by the gain or loss of particular metabolic or evasive capabilities will be investigated. The molecular mechanisms underlying the remarkable genetic plasticity of apicomplexan parasites, in particular the possible role of mobile and repetitive DNA elements in these processes will be explored. Finally, this study will reveal metabolic processes that are present, absent, or strikingly different in genera of this phylum relative to their human host. Taken together, this approach should shed considerable light on the basic biology of the Apicomplexa, reveal potential new therapeutic targets and test several important assumptions about how eukaryotic genomes evolve. The results of these studies will be shared with the larger research community via publication and deposition in community databases and Bioinformatics Resource Centers.